A comprehensive RNAi screen for genes effecting neuron degeneration and regeneration in C. elegans Neuronal degeneration and regeneration has been studied in humans and other vertebrate model systems for over 100 years and yet we still do not have a comprehensive molecular model nor an effective treatment to prevent degeneration or induce regeneration. Surprisingly, the powerful genetic model systems used so successfully to study body pattern formation, programmed cell death, neural development and many other important biological problems have not been used to study neuronal degeneration and regeneration. This is because it has been difficult to devise a robust screening assay for neural regeneration in either D. melanogaster or C. elegans. Recently, Hammarlund and myself made an observation that now makes it possible to screen for genes required for regeneration in C. elegans. We discovered that embryonic neurons lacking [unreadable]-spectrin develop normally (normal growth cone motility, pathfinding, and target recognition), but after hatching undergo a movement-induced axotomy followed by regeneration. This is a robust phenotype, with most commissural axons in each animal breaking and regenerating before the animal reaches adulthood. There is a progressive failure of regeneration as each cycle of axotomy and regeneration takes place so that the adult displays a severely abnormal nervous system. This well-characterized regeneration phenotype in C. elegans mimics the phenotype of mammalian neurons in response to axotomy. I propose to use RNAi knockdown to assay the function of every gene in the worm genome in the process of neuronal degeneration and regeneration. Recently, two genetic mutations were identified that sensitize neurons to RNAi. This sensitized genetic background has been used and validated in a successful large scale RNAi screen for genes that function in synaptic transmission. There is every reason to believe that this technique can be used to screen for genes that function in degeneration and regeneration using the [unreadable]-spectrin mutant phenotype as the basis for the assay. If successful, it would be the first unbiased "genetic" screen for genes functioning in neuron degeneration and regeneration and should identify novel genes as entry points for theurapies targeting neuronal degeneration and regeneration. This proposal represents the first unbiased "genetic" screen for genes functioning in neuron degeneration and regeneration in C. elegans. If successful it will identify novel genes as entry points for therapies aimed at the prevention neuronal degeneration and the induction of neuronal regeneration.